Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:32])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][C:5]2=O.Cl.[NH2:34][OH:35].CO.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.N1C=CC=CC=1>[OH:1][C:2]1[C:3]([CH3:32])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:29][CH:30]=1)([CH3:14])[CH2:6]/[C:5]/2=[N:34]\[OH:35]
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)/C(=N/O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2

Procedure:
A mixture of 5 g of 5-[4-(6hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione (prepared as described in Example 22 of copending U.S. Ser. No. 644,996), 3 g of hydroxylamine hydrochloride, 50 g of methanol and 3 g of pyridine was stirred for 1 week at room temperature. At the end of this time, ethyl acetate and an aqueous solution of potassium carbonate were added. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography, eluted with a 1:1 by volume mixture of hexane and ethyl acetate, to give the title compound, softening at 84°-100° C.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=2[C:5]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][CH:3]=1.[CH3:18][Sn](C)(C)C>CN(C)P(=O)(N(C)C)N(C)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:14]([CH:13]([C:5]1[C:6]2[N:7]([CH3:12])[C:8](=[O:11])[NH:9][C:10]=2[C:2]([CH3:18])=[CH:3][CH:4]=1)[CH2:16][CH3:17])[CH3:15]
Reactant: CCC(CC)c1ccc(Br)c2[nH]c(=O)n(C)c12
Reactant: C[Sn](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCC(CC)c1ccc(C)c2[nH]c(=O)n(C)c12
Yield: 57.1 %

Procedure:
A solution of 4-bromo-7-(1-ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (250 mg, 0.84 mmol), tetrakis(triphenylphosphine)palladium (194 mg, 0.168 mmol), tetramethyltin (1.16 mL, 8.4 mmol) in hexamethylphosphoric triamide (5 mL) was refluxed for 18 h. After cooling, the mixture was diluted with water and extracted with dichloromethane. The organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on a silica gel (n-hexane/ethyl acetate=90:10-50:50) to give the title compound (111 mg, 0.48 mmol, 57%).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([NH:20][CH2:21][CH3:22])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:23]>CO>[NH2:23][C:2]1[C:11]2[N:12]=[C:13]([NH:20][CH2:21][CH3:22])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: N
Reactant: CCNc1nc2c(Cl)nc3ccccc3c2n1CC(C)(C)O
Solvent: CO
Product: CCNc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O
Temperature: 150 °C

Procedure:
1-[4-Chloro-2-(ethylamino)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (2.49 g, 7.81 mmol) and ammonia (70 mL of a 7 N solution in methanol) were added to a high-pressure vessel, which was sealed and heated overnight in an oven at 150° C. An analysis by HPLC indicated the presence of starting material, and additional ammonia in methanol (10 mL) was added. The reaction was heated for four hours at 150° C. and cooled to ambient temperature. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel (eluting with 2-2.5% methanol in dichloromethane with 1% ammonium hydroxide added.) A portion of the product was recrystallized from methanol, isolated by filtration, and washed with cold methanol to provide 496 mg of 1-[4-amino-2-(ethylamino)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as white needles, mp 233-235° C.
Reaction SMILES: [CH3:1][C@@H:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:5]([C:14]([O:16][CH2:17][C:18](=[O:38])[C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[CH:30]=[C:29]5[CH2:32][CH2:33][CH2:34][C:35](=[O:36])[C:28]5=[CH:27][C:26]=4[O:25][CH2:24][C:23]=3[CH:37]=2)=[O:15])[CH2:4][CH2:3]1.[Br-:39].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl.CO.Cl>[CH3:1][C@@H:2]1[N:6]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[C@H:5]([C:14]([O:16][CH2:17][C:18]([C:19]2[CH:20]=[CH:21][C:22]3[C:31]4[CH:30]=[C:29]5[CH2:32][CH2:33][CH:34]([Br:39])[C:35](=[O:36])[C:28]5=[CH:27][C:26]=4[O:25][CH2:24][C:23]=3[CH:37]=2)=[O:38])=[O:15])[CH2:4][CH2:3]1
Reactant: [Br-]
Reactant: C[C@H]1CC[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCCC4=O)N1C(=O)OC(C)(C)C
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: ClCCl
Product: C[C@H]1CC[C@@H](C(=O)OCC(=O)c2ccc3c(c2)COc2cc4c(cc2-3)CCC(Br)C4=O)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(2S,5S)-1-tert-butyl 2-(2-oxo-2-(8-oxo-8,9,10,11-tetrahydro-5H-dibenzo[c,g]chromen-3-yl)ethyl) 5-methylpyrrolidine-1,2-dicarboxylate (1.29 g, 2.48 mmol) was dissolved in a solution of DCM (17.5 mL) and MeOH (7 mL), then treated with pyridinium tribromide (873 mg, 2.73 mmol). After stirring at RT for 1 h, the reaction mixture was diluted with DCM and 10% HCl, and extracted with DCM. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure and the crude material was carried on without further purification.
Reaction SMILES: [CH:1]([C:3]1[O:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1)=O.Cl.[NH2:12]O.C(OC(=O)C)(=O)C.Cl>O.N1C=CC=CC=1>[C:1]([C:3]1[O:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1)#[N:12]
Reactant: NO
Reactant: O=Cc1ccc(C(=O)O)o1
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: N#Cc1ccc(C(=O)O)o1
Temperature: 85 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
To a flask with a stir bar and Vigreaux column under Ar was added 2-formyl-5-furancarboxylic acid (2.8 g, 20 mmol), hydroxylamine hydrochloride (2.7 g, 40 mmol), and dry pyridine (50 mL). The mixture was heated to 85° C., acetic anhydride (40 mL) was added and the mixture was stirred for 3 h. After cooling to 60° C., water (250 mL) was added and the mixture was stirred at RT for 70 h. The mixture was acidified to pH 2 with concentrated hydrochloric acid and extracted with 3:1 dichloromethane-isopropanol (8×100 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anh sodium sulfate and concentrated in vacuo to afford the title compound as a tan solid (1.26 g, 46%). 1H-NMR (CD3OD; 400 MHz): δ 14.05 (br s, 1H), 7.74 (d, 1H, J=3.8 Hz), 7.42 (d, 1H, J=3.8 Hz).
Reaction SMILES: [ClH:1].[CH:2](=[N:9][CH2:10][CH2:11][NH:12][S:13]([N:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H]>CO.[Pd]>[ClH:1].[CH2:2]([NH:9][CH2:10][CH2:11][NH:12][S:13]([N:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: CN(C)S(=O)(=O)NCCN=Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)S(=O)(=O)NCCNCc1ccccc1
Yield: 92.8 %

Procedure:
A solution of 3.0 g (0.011 mole) of N-benzylidene-2-[N'-[(dimethylamino)sulfonyl]amino]ethylamine hydrochloride in 100 ml of methanol was hydrogenated, at 40 psi, over 0.3 g of 10% Pd-C catalyst until hydrogen uptake ceased (20 min.). The mixture was filtered and concentrated under reduced pressure to provide 3.0 g of crude product. The NMR spectrun was consistent with the assigned structure and the crude product was utilized directly without further purification.
Reaction SMILES: O.[C:2](=[O:4])=O.[CH2:5]=[CH:6][CH:7]=[CH2:8].[C:9](O)(C)([CH3:11])[CH3:10]>>[CH:2]([OH:4])=[CH:5][CH:6]=[CH:7][CH2:8][CH2:10][CH2:9][CH3:11]
Reactant: CC(C)(C)O
Reactant: O=C=O
Reactant: C=CC=C
Solvent: O
Product: CCCCC=CC=CO
Yield: 70 %

Procedure:
For example, when a mixture of carbon dioxide, water, butadiene, dioxane solvent and palladium catalyst is reacted under certain conditions, a 50-60 percent yield of octadienol is realized compared to the 10 percent yield of octadienol that is obtained in the absence of carbon dioxide. In t-butanol solvent, a mixture of water, carbon dioxide, butadiene, solvent and catalyst yields at least 70 percent octadienol compared to a 10 percent yield in the absence of carbon dioxide. The total reaction is outlined below. ##SPC1##
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].N1C=CC=CC=1.[CH3:20][O:21][C:22]1[CH:43]=[CH:42][C:25]([C:26](Cl)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1>O1CCOCC1>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([C:26]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13])([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:25]2[CH:42]=[CH:43][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[CH:32][CH:31]=1
Reactant: OCCOCCOCCOCCO
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COc1ccc(C(OCCOCCOCCOCCO)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
Tetraethyleneglycol (14.0 g, 72 mmol) was coevaporated with dry pyridine (2×50 mL), dissolved in dry dioxane and 4,4′-dimethoxytrityl chloride (8.0 g, 23.6 mmol) was added portion-wise to the stirred solution. The reaction was monitored by TLC. After overnight stirring at ambient temperature, the reaction mixture was evaporated and dissolved in CH2Cl2 (200 mL), and washed with saturated aq. NaHCO3 (3×100 mL) and brine (100 mL). The organic phase was dried over Na2SO4 and concentrated. Purification on silica gel column using a stepwise gradient of MeOH (0 to 10%) in CH2Cl2 containing 0.2% pyridine yielded 8.5 g (73%) of the title compound.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[NH:8][CH:7]=1)([O-])=O>O=[Pt]=O.CO>[CH3:18][O:17][C:15]([C:12]1[CH:13]=[C:14]2[C:9]([NH:8][CH:7]=[C:6]2[CH2:5][CH2:4][NH2:1])=[CH:10][CH:11]=1)=[O:16]
Reactant: COC(=O)c1ccc2[nH]cc(CC[N+](=O)[O-])c2c1
Agent: O=[Pt]=O
Solvent: CO
Product: COC(=O)c1ccc2[nH]cc(CCN)c2c1

Procedure:
Combine 3-(2-nitroethyl)-5-methoxycarbonyl-1H-indole (280 mg, 1.1 mmol), PtO2 (200 mg) and 15 mL MeOH and hydrogenate at atmospheric pressure overnight. Filter reaction mixture through a pad of celite, concentrate the filtrate, and chromatograph on silica gel eluting with 5% MeOH in CHCl3 mixed with conc. NH4OH to give the title compound as an oil: ISMS 219 (M+1); 1H NMR (CDCl3) 9.01 (s, 1H), 8.36 (s, 1H), 7.88–7.85 (m, 1H), 7.32–7.24 (m, 1H), 7.05 (s, 1H), 3.91 (s, 3H), 3.05–3.01 (m, 2H), 2.93–2.89 (m, 2H), 1.22 (bs, 2H).
Reaction SMILES: Cl.[NH2:2][OH:3].[Cl:4][C:5]1[CH:6]=[C:7]([C@@H:15]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[C:16]([NH:18][C:19]2[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]>CO.N1C(C)=CC=CC=1C>[Cl:4][C:5]1[CH:6]=[C:7]([C@@H:15]([CH2:26][CH:27]2[CH2:32][CH2:31][C:30](=[N:2][OH:3])[CH2:29][CH2:28]2)[C:16]([NH:18][C:19]2[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][N:20]=2)=[O:17])[CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12]
Reactant: Cc1cnc(NC(=O)[C@H](CC2CCC(=O)CC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Reactant: NO
Agent: Cl
Solvent: Cc1cccc(C)n1
Solvent: CO
Product: Cc1cnc(NC(=O)[C@H](CC2CCC(=NO)CC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 244.4 %

Procedure:
A solution of hydroxylamine hydrochloride (17.0 mg, 0.24 mmol) in methanol (0.5 mL) and 2,6-lutidine (0.5 mL) was treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-methyl-pyrazin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (prepared as in Example 62, 34 mg, 0.066 mmol). The reaction mixture was stirred at 25° C. for 30 min and was then concentrated in vacuo to remove methanol. The resulting residue was suspended in ethyl acetate (10 mL), washed with water (1×5 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 12M, Silica, 65/35 hexanes/ethyl acetate to ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-hydroxyimino-cyclohexyl)-N-(5-methyl-pyrazin-2-yl)-propionamide (75 mg, 100%) was a white foam: [α]23589=−30.0° (c=0.32 chloroform); EI-HRMS m/e calcd for C21H25ClN4O4S (M+H)+ 465.1358, found 465.1365.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=C[C:14]([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH:34]([CH3:36])[CH3:35].C[N:38](C)C=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH2:33][CH:34]([CH3:36])[CH3:35])=[C:6]([CH:24]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:38][C:14]([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: CC(C)CBr
Reactant: CCCCOC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2O)nc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCOC(=O)c1ccc(N(CC)Cc2cc(Br)ccc2OCC(C)C)nn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
Butyl 6-[N-(5-bromo-2-hydroxybenzyl)-N-ethylamino]pyridine-3-carboxylate (reference example 3) (1.12 g, 2.76 mmol) in dimethylformamide (16 ml) was treated with potassium carbonate followed by 1-bromo-2-methylpropane (0.16 ml, 770 mg, 5.6 mmol) and stirred at ambient temperature overnight. TLC showed reaction to be incomplete so further potassium carbonate (1.12 g) and 1 -bromo-2-methylpropane were added and the mixture stirred at ambient temperature over two days. The mixture was then evaporated to low bulk and the residue purified directly by MPLC to give the title compound as a colourless gum (1.26 g, 98%).
Reaction SMILES: O[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:17])=O.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Cl:17][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cnc1O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1cc(C(F)(F)F)cnc1Cl
Temperature: 80 °C

Procedure:
2-Hydroxy-3-nitro-5-trifluoromethylpyridine (8.8 g, 42.3 mmol) was added to a mixture of phosphorous oxychloride (4.2 mL, 45.9 mmol) and phosphorous pentachloride (9.6 g, 46.1 mmol) at 60° C. The reaction mixture was then heated under nitrogen at 80° C. overnight. The resulting dark product mixture was allowed to cool to room temperature and was poured into ice/water. The mixture was extracted with ether and the ether extract was washed with water and brine. After drying over magnesium sulfate, the solvent was removed to leave a dark oil which was subjected to flash chromatography on silica gel eluting with chloroform. Fractions containing only the desired product were combined and concentrated to leave a brown oil (5.0 g, 52%). 1H NMR (DMSO-d6): δ9.20 (s, 1H), 9.07 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH2:13][CH2:14][O:15][C:16]3[C:17]([N:22]4[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]4)=[N:18][CH:19]=[CH:20][N:21]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:35][C:36](OC(C)=O)=[O:37]>N1C=CC=CC=1>[C:36]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH2:13][CH2:14][O:15][C:16]3[C:17]([N:22]4[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26][CH2:27]4)=[N:18][CH:19]=[CH:20][N:21]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1)(=[O:37])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCOc2cccc3ccc(N)nc23)CC1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2cccc(OCCOc3nccnc3N3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The product obtained in Step 1 (502 mg, 1.08 mmol) was dissolved in pyridine. Ac2O (0.42 mL, 4.45 mmol) was added, and the reaction mixture was stirred under inert atmosphere at room temperature for 5 h. Concentration in vacuo afforded a yellow oil, which was purified by column chromatography using EtOAc/Et3N (95:5) as eluent to give the title product as a yellow solid: yield 531 mg (97%); MS m/z 509 (M+H)+. Anal. (C26H32N6O5.0.4 H2O) C, H, N.
Reaction SMILES: O.[S-2].[Na+].[Na+].[CH3:5][N:6]([CH2:8][CH:9]([C:18]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:10]1[CH:11]=[CH:12][C:13]([O:16]C)=[CH:14][CH:15]=1)[CH3:7].C(OC(=O)C)C.O>CN1CCCC1=O>[CH3:5][N:6]([CH2:8][CH:9]([C:18]1([OH:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:10]1[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=1)[CH3:7]
Reactant: COc1ccc(C(CN(C)C)C2(O)CCCCC2)cc1
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CN(C)CC(c1ccc(O)cc1)C1(O)CCCCC1
Temperature: 145 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
A mixture of 5.7 g of sodium sulfide hydrate, and 6 mL of 1-methylpyrrolidone was heated to 145° C. under nitrogen, and then 3.5 g of venlafaxine dissolved in 6 mL of 1-methylpyrrolidone was added. The mixture was stirred and heated at 145° C. under nitrogen, approx. 3.5 g of liquid was distilled off. Reaction mixture was heated at 145° C. for 30 hours, then it was cooled and mixed with 70 mL of ethylacetate and 50 mL of water. The mixture was placed into a refrigerator and after 2 hours crystals were filtered and dried to give 2.5 g of desvenlafaxine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:23])=[C:4]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[C:5]([I:17])=[C:6]([C:15]=1[I:16])[C:7]([NH:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])=[O:8].[C:24](OC(=O)C)(=[O:26])[CH3:25].C(Cl)Cl.[C:34](OCC)(=[O:36])[CH3:35]>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]([I:23])=[C:4]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[C:5]([I:17])=[C:6]([C:15]=1[I:16])[C:7]([NH:9][CH2:10][CH:11]([O:14][C:34](=[O:36])[CH3:35])[CH2:12][O:13][C:24](=[O:26])[CH3:25])=[O:8]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)NCC(O)CO)c1I
Reactant: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I
Reaction time: 10 h

Procedure:
5-Amino-3-acetoxymethyl-N-(2,3-dihydroxypropyl)-2,4,6-triiodobenzamide (2.13 g, 3.23 mmol) was dissolved in pyridine (12 ml). Acetic anhydride (10 ml) was added dropwise with efficient stirring. Stirring was continued at ambient temperature for 10 h. The reaction mixture was then evaporated to a solid residue, which was taken up in chloroform (70 ml). The organic phase was washed with aqueous hydrochloric acid (1M) until pH=2, then twice with water (40 ml) and last with a saturated solution of sodium hydrogen carbonate until pH=8-9. After drying (Na2SO4), the solvent was evaporated to yield a dark solid residue. This was taken up in a mixture of methylene chloride/ethyl acetate (90/10) and eluted through a pad of alumina. After evaporation of the solvent, 2.1 g (87%) of a white crystalline residue was left.
Reaction SMILES: [CH3:1][C:2]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15](C3C=CN=C(C(OC)=O)C=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9].BrC1C=CN=C(C(OC)=O)C=1.Br[C:47]1[CH:48]=[N:49][N:50]([CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[C:55]([O:59][CH3:60])[CH:54]=2)[CH:51]=1>>[CH3:1][C:2]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15]([C:47]3[CH:48]=[N:49][N:50]([CH2:52][C:53]4[CH:58]=[CH:57][CH:56]=[C:55]([O:59][CH3:60])[CH:54]=4)[CH:51]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: COC(=O)c1cc(-c2cccc3c2CCCN3C(=O)CCCOc2cccc(C)c2C)ccn1
Reactant: COc1cccc(Cn2cc(Br)cn2)c1
Agent: COC(=O)c1cc(Br)ccn1
Product: COc1cccc(Cn2cc(-c3cccc4c3CCCN4C(=O)CCCOc3cccc(C)c3C)cn2)c1

Procedure:
The title compound was prepared using a procedure analogous to methyl 4-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)picolinate except that methyl 4-bromopicolinate was replaced with 4-bromo-1-(3-methoxybenzyl)-1H-pyrazole. LCMS, [M+H]+=510.4.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5](C(OCCCC2C=CC=CC=2)=O)[C@H:4]([C:20]([O-:22])=[O:21])[CH2:3]1.[H][H].[CH3:25][CH2:26]O>[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][NH:5][C@H:4]([C:20]([O:22][CH2:25][CH3:26])=[O:21])[CH2:3]1
Reactant: CCO
Reactant: [H][H]
Reactant: CN1CCN(C(=O)OCCCc2ccccc2)[C@H](C(=O)[O-])C1
Agent: [Pd]
Product: CCOC(=O)[C@@H]1CN(C)CCN1

Procedure:
A suspension of 2.04 (6.66 mmol) 1-benzyl-2-ethyl(S)-4-methyl -piperazine-1,2-dicarboxylate and 200 mg 10% Pd/C in 100 mL EtOH was hydrogenated at 50° C. and 3447 hPa hydrogen pressure for 6 h. The catalyst was filtered off, the filtrate was evaporated to dryness i. vac. and the residue was further reacted without any purification.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:11]=[C:10](Cl)[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[C:13](=O)([O-])[O-].[Na+].[Na+]>CO.O>[NH2:2][C:3]1[CH:11]=[CH:10][C:9]([Cl:1])=[CH:8][C:4]=1[C:5]([O:7][CH3:13])=[O:6]
Reactant: Cl
Reactant: Nc1cc(Cl)ccc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1cc(Cl)ccc1N
Yield: 57.3 %

Procedure:
A solution of hydrogen chloride (27.1 g) in methanol (192.2 g) is stirred at room temperature and 2-amino-4-chlorobenzoic acid (25 g) is added. The mixture is heated under reflux for 10 hours, then cooled and neutralised with a solution of sodium carbonate (20 g) in water (200 ml). The solid is filtered off, washed with water, and dried in vacuo at 65° C. to give methyl 2-amino-5-chlorobenzoate (15.5 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=[O:5])[CH3:4].[F:7][C:8]([F:12])([F:11])[S:9]Cl>>[F:7][C:8]([F:12])([F:11])[S:9][C:2]([CH3:6])([CH3:1])[C:3](=[O:5])[CH3:4].[F:7][C:8]([F:12])([F:11])[S:9][CH2:4][C:3](=[O:5])[CH:2]([CH3:6])[CH3:1]
Reactant: FC(F)(F)SCl
Reactant: CC(=O)C(C)C
Product: CC(=O)C(C)(C)SC(F)(F)F
Product: CC(C)C(=O)CSC(F)(F)F

Procedure:
Using the method described in Example 3, 3-methyl-2-butanone was reacted with trifluoromethanesulfenyl chloride to provide a reaction product which was distilled. The product had a boiling point of 51° to 84°C/48 mm. Vapor phase chromatography of this distillate showed two products to be present in major quantities. Fractional distillation of this product provided 3-trifluoromethylthio-3-methyl-2-butanone, b.p. 68°C/54 mm Hg and 1-trifluoromethylthio-3-methyl-2-butanone, b.p. 84°C/54 mm Hg. The structures of these compounds were determined by spectral and elemental analyses.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.Cl.[F:11][C:12]([F:17])([F:16])[C@@H:13]([NH2:15])[CH3:14].CCN(CC)CC>O=S(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[N:3]=[C:4]([C:7]([NH:15][C@@H:13]([CH3:14])[C:12]([F:17])([F:16])[F:11])=[O:9])[S:5][CH:6]=1
Reactant: C[C@H](N)C(F)(F)F
Reactant: O=C(O)c1nc(Br)cs1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1nc(Br)cs1)C(F)(F)F
Reaction time: 8 h
Yield: 53.2 %

Procedure:
To the mixture of 4-bromothiazole-2-carboxylic acid (80 g, 1.0 eq.) in SOCl2 (300 ml) was added DMF (10 drops). It was refluxed for 5 hours and concentrated. The residue was dissolved in DCM (300 ml) and added to the solution of (S)-1,1,1-trifluoropropan-2-amine hydrochloride (60.5 g, 1.05 eq.) with Et3N (117 g, 3.0 eq.) at 0° C. It was stirred overnight. TLC and LCMS showed the reaction was complete. It was quenched with water and extracted with DCM. The organic phase was dried, filtered and concentrated. The residue was purified by column to obtain 62 g (53% y) of (S)-4-bromo-N-(1,1,1-trifluoropropan-2-yl)thiazole-2-carboxamide.